Pulmonary surfactants are found at the alveolar surface and are essential for breathing. They consist of a complex mixture of phospholipids (85%), neutral lipids (5%), and several specific surfactant proteins (5%) which reduce surface tension at the alveolar surface, allowing for rapid gaseous exchange. The unique spreading properties of the pulmonary surfactant reduce surface tension, thereby promoting lung expansion (also known as compliance) during inspiration, and preventing lung collapse during expiration.
Without surfactant, the air sacs or alveoli of the lungs collapse and are unable to absorb sufficient oxygen. This can manifest as an inhibition of gas exchange in the lungs, causing a condition known as hyaline membrane disease (HMD), also known as respiratory distress syndrome (RDS). This condition occurs most frequently in premature infants, but also often occurs in older children and adults. Older children and adults may present with a wide spectrum of lung conditions which include, but are not limited to, hydrocarbon (e.g. paraffin) poisoning, near-drowning, HIV/AIDS-related lung diseases, adult respiratory distress syndrome (ARDS) or acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD), tuberculosis (TB), and severe acute respiratory syndrome (SARS).
The observation that preterm infants with RDS suffer from an alveolar surface-active material deficiency led to the treatment of the condition with exogenous surfactant replacements, and various pulmonary surfactants are now commercially available, such as those listed below in Table 1. These include mammalian-derived or natural surfactants containing surfactant proteins and synthetic protein-free lipid mixtures:
TABLE 1A selection of commercially available pulmonary surfactantsGeneric nameBrand nameManufacturerBeractantSurvanta ®Abbott Laboratories (USA)Surfactant-TASurfacten ®Tokoyo Tanabe (Japan)Porcine surfactantCurosurf ®Chiesi Pharmaceuticals(Italy)Calf pulmonaryInfasurf ®Forest Laboratories (USA)surfactant (CLSE)SF-RI 1Alveofact ®Boehringer (Germany)Artificial lungPneumactant ®Britannia Pharmaceuticalsexpanding compound(UK)(ALEC)Colfosceril palmitateExosurf ®Glaxo Wellcome Co (USA)hexadecanol, tyloxapol
Mammalian-derived surfactant, also referred to herein as native or natural pulmonary surfactant, consists mainly of phospholipids, the major phospholipid being dipalmitoyl phosphatidylcholine (DPPC). It also includes phosphatidyl glycerol (PG) and surfactant proteins (SP) A, B, C, and D. The formation of tubular myelin, which is the active in vivo extracellular form of native pulmonary surfactant, requires the presence of DPPC, PG, SP-A, SP-B, and calcium. SP-B and SP-C are believed to assist natural surfactants to manifest superior in vivo and in vitro surface behaviour (Dizon-Co et al 1994). Of the various protein components of the pulmonary surfactant, SP-B appears to have an essential function in maintaining alveolar expansion. Indeed, simply supplementing artificial phospholipids with hydrophobic SP-B and/or SP-C, whether from native or recombinant sources, has been shown to result in improved in vivo and in vitro function (Dizon-Co et al 1994; Ikegami and Jobe 1998; Davis et al 1998). The absence of SP-B has been shown to result in both a deficiency in SP-C as well as causing lethal respiratory failure in full term infants (Nogee et al 1993; Clark et al 1995).
Mammalian-derived surfactants have been available for many years, but are expensive and their therapeutic application has been focused upon use in HMD/RDS occurrence in premature infants. These surfactant formulations usually contain proteins derived from bovine or porcine sources and hence pose a potential risk for the transmission of animal-associated pathogens.
Initial synthetic protein-free lipid surfactants, such as Exosurf®, have demonstrated inferior performance both in animal experiments and in human infant trials, when compared to surfactant formulations containing protein (Grossman et al 1984; Cummings et al 1992; Halliday 1997; Ainsworth et al 2000). Later synthetic surfactants, such as Lucinactant (Surfaxin®, Discovery Laboratories, Philadelphia), containing sinapultide KL4 have demonstrated superior performance with regard to the risk of mortality, chronic lung disease and other morbidities associated with prematurity in infants having HMD/RDS or at risk of developing the condition. However, in two trials in which such protein-containing synthetic surfactants were compared with animal-derived surfactant extract, no statistical difference in death or chronic disease was noted (Cochrane Syst Review, 2007). Furthermore, Lucinactant is a gel at room temperature and must first be warmed before use for it to be in a liquid form. Lucinactant has not yet been approved by the FDA for treatment in neonatal HMD/RDS.
The efficacy of the currently commercially available preparations has been assessed both in animal models of RDS and in clinical trials involving human infants with the same condition. Overall, the available protein-free synthetic formulations demonstrate inferior performance in vivo compared to that of protein-containing natural formulations. However, the safety of surfactants containing foreign protein has been questioned. Further drawbacks of surfactant preparations derived from animal tissues include the complexity of the manufacturing and sterilization processes required. Reconstituted surfactants generally include added hydrophobic proteins, either isolated from animal tissues or obtained through recombinant techniques, or synthetic peptidic derivatives of such proteins. The properties and activity of the reconstituted surfactants therefore greatly depend not only upon the h composition of the phospholipid mixture but also upon the peptide/protein components.
There is therefore a need for a synthetic pulmonary surfactant composition which has surface properties equivalent to those of natural surfactant.